Ku70, Ku80, sClusterin: a “cluster” of predicting factors for neoadjuvant chemoradiotherapy treatment response in patients affected by locally advanced rectal cancer

Purpose: Identification of predictive biomarkers for neoadjuvant chemoradiotherapy (CRT) is a current clinical need. The heterodimer Ku70/80 plays a critical role in DNA repair and cell death induction after damage. Aberrant expression and localization of these proteins fail to control DNA repair and apoptosis. sClusterin is the Ku70 partner that sterically inhibits Bax dependent cell death after damage in some pathological condition. This study seeks to evaluate the molecular relevance of Ku70-80/Clu as predicting molecular “cluster” for neoadjuvant chemoradiotherapy treatment response in locally advanced rectal cancer (LARC) patients. Methods: Patients enrolled in this study underwent preoperative chemoradiotherapy, followed by surgical excision. Retrospective study based on individual response, evaluated by Computer Tomography and Diffusion-weighted, identified the responder (56%) and no responder patients (44%). Ku70-80 and Clu expression were observed in biopsies obtained before treatment and after treatment with neoadjuvant CRT, from the same patients diagnosed with LARC. In vitro study pre and post irradiation were also performed on radioresistant (SW480) and radiosensible (SW620) colorectal cancer cell lines,mimicking sensible or resistant tumor behaviour. Results: We found a conventional nuclear localization of Ku70-80 in pretherapeutic tumoral biopsies of responder patients, in agreement with the role in DNA repair and apoptosis regulator. On the contrary in no responder population we observed an unconventional overexpression of Ku70 in the cytoplasm (p<0,001). In this context we found also sClu overexpressed in the cytoplasm according to its role of stabilizer of Bax-Ku70 complex, inhibiting Bax dependent apoptosis. Strikingly Ku80 in these tumour tissues was lost (p<0,005). In vitro test on colon cancer cells, finally confirm the results observed in tumor biopsies proving that Ku70-80/Clu deregulation are extensively involved in the resistance mechanisms. Conclusion: These results strongly suggest a potential role of these proteins as new prognostic tool to predict the chemoradiation response in locally advanced rectal cancer.